Impact of Warhead Modulations on the Covalent Inhibition of SARS-CoV2 Mpro Explored by QM\/MM Simulations
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Título
Impact of Warhead Modulations on the Covalent Inhibition of SARS-CoV2 Mpro Explored by QM\/MM SimulationsAutoría
Fecha de publicación
2021-12-26Editor
American Chemical SocietyCita bibliográfica
Marti S, Arafet K, Lodola A, Mulholland A, Swiderek K, Moliner V. Impact of warhead modulations on the covalent inhibition of SARS-CoV-2 Mpro explored by QM/MM simulations. ACS Catal. 2022, 12, 1, 698–708Tipo de documento
info:eu-repo/semantics/articleVersión de la editorial
https://pubs.acs.org/doi/abs/10.1021/acscatal.1c04661#Versión
info:eu-repo/semantics/submittedVersionPalabras clave / Materias
Resumen
The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus-2, SARS-CoV-2, shows the need for effective antiviral treatments. Here, we present a simulation study of the inhibition of the SARS-CoV-2 ... [+]
The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus-2, SARS-CoV-2, shows the need for effective antiviral treatments. Here, we present a simulation study of the inhibition of the SARS-CoV-2 main protease (Mpro), a cysteine hydrolase essential for the life cycle of the virus. The free energy landscape for the mechanism of the inhibition process is explored by QM/MM umbrella sampling and free energy perturbation simulations at the M06-2X/MM level of theory for two proposed peptidyl covalent inhibitors that share the same recognition motif but feature distinct cysteine-targeting warheads. Regardless of the intrinsic reactivity of the modeled inhibitors, namely a Michael acceptor and a hydroxymethyl ketone activated carbonyl, our results confirm that the inhibitory process takes place by means of a two-step mechanism, in which the formation of an ion pair C145/H41 dyad precedes the protein–inhibitor covalent bond formation. The nature of this second step is strongly dependent on the functional groups in the warhead: while the nucleophilic attack of the C145 sulfur atom on the Cα of the double bond of the Michael acceptor takes place concertedly with the proton transfer from H41 to Cβ, in the compound with an activated carbonyl, the sulfur attacks the carbonyl carbon concomitant with a proton transfer from H41 to the carbonyl oxygen via the hydroxyl group. An analysis of the free energy profiles, structures along the reaction path, and interactions between the inhibitors and the different pockets of the active site on the protein shows a measurable effect of the warhead on the kinetics and thermodynamics of the process. These results and QM/MM methods can be used as a guide to select warheads to design efficient irreversible and reversible inhibitors of SARS-CoV-2 Mpro. [-]
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ACS Catal. 2022, 12, 1Entidad financiadora
Spanish Ministerio de Ciencia, Innovación y Universidades | Generalitat Valenciana | Universitat Jaume I | Mare Nostrum of the Barcelona Supercomputing Center | EPSR, CCPBioSim
Código del proyecto o subvención
PGC2018-094852−B-C21 | PID2019-107098RJ-I00 | AICO/2019/195 | SEJI/2020/007 | UJI-A2019-04 | UJI-B2020-03 | APOSTD/2020/015 | QSB-2021-1-0007 | EP/M022609/1
Derechos de acceso
Copyright © 2021 American Chemical Society
info:eu-repo/semantics/openAccess
info:eu-repo/semantics/openAccess
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